Orthomyxoviridae are RNA viruses, the most prominent members being influenza virus species. Influenza A and B virus are the two types of influenza viruses that cause epidemic human disease. They are typically spread from person to person, primarily through respiratory droplet transmission.
The paramyxoviridae family includes respiratory syncytial virus (RSV), parainfluenza virus and metapneumavirus. RSV and parainfluenza virus infections may cause serious respiratory infections in infants and young children but may also cause severe disease in elderly persons and adults having an impaired immune system.
Among the human parainfluenza virus species four members are known to cause serious respiratory diseases in children for which presently no effective prevention or therapy is available, the four members being parainfluenza virus types 1 through 4. Parainfluenza virus and RSV outbreaks are believed to contribute substantially to increased hospitalization and mortality rates. Patients with impaired immune, cardiac, or pulmonary systems are at increased risk of running into serious complications following a paramyxovirus infection and will therefore particularly benefit from an antiviral therapy.
Respiratory syncytial virus (RSV), which is the most wide-spread respiratory pathogen typically afflicting individuals during infancy and early childhood worldwide, causes yearly outbreaks of pneumonia and bronchiolitis during winter time and early in spring. RSV bronchiolitis and pneumonia require hospitalization of hundreds of thousands of infants every year. Passive protection against RSV is available at least in part at a reported 55% success rate upon monthly intramuscular injection of the humanized monoclonal anti-RSV antibody palivizumab (Synagis®).
The coronaviridae family includes coronavirus and torovirus. Coronaviruses are known to infect the upper respiratory tract and the gastrointestinal tract in mammals and birds. It is believed that coronaviruses cause a high percentage of all common colds in human adults.
Adenoviridae are DNA viruses which typically infect the upper respiratory tract. At present, more than 50 different serotypes of human adenovirus are known, grouped in six subtypes A to F, which are responsible for 5-10% of upper respiratory infection in children.
In view of the aforementioned it is believed that there exists a strong need for a potent antiviral pharmaceutical composition that is easily applicable and effective in the prevention or treatment of respiratory viral infections caused by members of the paramyxoviridae, orthomyxoviridae, coronaviridae and/or adenoviridae families.
Sulphated polysaccharides including carrageenans and fucoidan have been known for their antiviral efficacy for decades. Accordingly, the prior art is replete with scientific articles on the antiviral effects of carrageenans. In a most interesting review, Gonzalez M. E. et al. (1987, Antimicrob. Agents Chemother. 31, 1388-1393) report an antiviral efficacy of different sulphated polysaccharides including iota-carrageenan against several animal viruses. Iota-carrageenan showed antiviral activity against the enveloped viruses HSV-1, HSV-2, Semliki Forest virus (SFV), vaccinia virus and African swine fever virus (ASF) and against the naked encephalomyocarditis (EMC) virus. Iota-carrageenan had no effect on the enveloped viruses vesicular stomatitis virus (VSV) and measles virus and on the naked viruses polio virus type 1 and adenovirus type 5.
U.S. Pat. No. 4,783,446 discloses an antiviral activity of iota-, kappa- and lambda-carrageenan against retroviral infection, in particular against human T-cell leukemia virus (HTLV) III infection.
WO 88/06396 discloses a method for the treatment of retroviral infections, including infection with HIV, by administering a carrageenan or a mixture of carrageenans.
Girond et al. (1991, Research Virol. 142, 261-270) disclose that sulphated polysaccharides like iota-, kappa-, and lambda-carrageenan have an effective inhibitory activity against the replication of hepatitis A virus (HAV).
Baba M. et al. (1988, Antimicrob. Agents Chemother. 32, 1742-1745) disclose several sulphated polysaccharides including dextran sulphate, pentosan polysulphate, fucoidan and carrageenan as being potent inhibitors of HSV-1, HSV-2, human cytomegalovirus (CMV), vesicular stomatitis virus (VSV), Sindbis virus and HIV-1. On the other hand, these sulphated polysaccharides were tested to be inactive against coxsackievirus, poliovirus and parainfluenza virus.
EP 0293826 discloses the therapeutic and prophylactic application of sulfated polysaccharides such as fucoidan and carrageenans to inhibit HIV-1 in vitro.
U.S. Pat. No. 5,658,893 discloses a method for inhibiting rotavirus infection of human cells by contacting the rotavirus with lambda-carrageenan. It is further disclosed that iota- and kappa-carrageenan did not exhibit anti-rotaviral activity.
US 2003/181415 A discloses that sulphated polysaccharides, including cellulose sulphate, are known to be effective against various enveloped viruses and in particular against herpes simplex virus (HSV), Papilloma viruses and HIV.
Fucoidan is a sulphated polysaccharide mainly extracted from various species of brown seaweed. There are two types of pharmacological grade fucoidans available on the market, a high molecular weight fucoidan (HMWF) fraction having an average molecular weight ranging from about 1,000,000 to 2,000,000 Da (e.g. Kraeber, Germany) and a low molecular weight fucoidan (LMWF) fraction having an average molecular weight of 8,200 Da.
F-fucoidan is mainly composed of sulphated esters of fucose, while U-fucoidan is comprised of about 20% of glucuronic acid.
Carrageenan is a generic term for linear sulphated galactose-based polysaccharides extracted from seaweed (rhodophyceae). It is mainly used as a thickener, gelling agent, stabilizer or emulsifier in pharmaceutical and food products. There exist more than 10 structurally different carrageenans, their nature depending on the seaweed genus from which they are extracted. The three main types are iota-, kappa- and lambda-carrageenan, which differ slightly in their structure and degree of sulphatation. Iota-carrageenan is a soft-gel forming sulphated galactan predominantly extracted from red seaweed Gigartina stellata and Chondrus crispus. Kappa-carrageenan yields strong, rigid gels and is predominantly produced from Kappaphycus cottonii. Lambda-carrageenan, which is the most common form, is frequently used to thicken dairy products.
Despite the long known antiviral activity of carrageenans against viruses such as, e.g. HIV, HSV, HAV, HTLV, or HPV, the mechanism of how carrageenans exhibit antiviral activity still needs further clarification.
For example, Baba M. et al. (1988, Antimicrob. Agents Chemother. 32, 1742-1745) speculate that sulphated polysaccharides including kappa- and lambda-carrageenan inhibit or at least contribute to the inhibition of virus adsorption of several enveloped viruses to the host cell surface. Similarly, US 2005/0261240 assumes that carrageenan may non-specifically bind to a virus thereby blocking virus receptor sites. Damonte E. B. et al. (2004, Curr. Med. Chem. 11, 2399-2419) disclose that sulphated polysaccharides may mimic cellular heparin sulphate and therefore block viral receptor sites responsible for the initial interaction between virus and host cell, whereas Gonzalez M. E. et al. (1987, Antimicrob. Agents Chemother. 31, 1388-1393) found, using labeled virion particles, that HSV-1 virions are internalized even in the presence of high concentrations of iota-carrageenan. They suggest that at least for HSV-1 carrageenan inhibits a step in virus replication subsequent to virus attachment and entry into the cell but still prior to the synthesis of late viral proteins.
Turner E. V. and Sonnenfeld G. (1979, Infection and Immunity 25, 467-469) disclose an antiviral activity of lambda- but not kappa-carrageenan against bovine vesicular stomatitis virus which antiviral activity is due to immunomodulation, i.e. to the induction of interferon.
In conclusion, it can be summarized taking the words of U.S. Pat. No. 5,658,893, that “in view of the different responses by different viruses to sulphated polysaccharides, it is clear that the response of a particular virus to carrageenan cannot be predicted with certainty without experimentation. The mechanism by which sulphated polysaccharides, particularly the carrageenans, inhibit viral replication and infectivity may not be uniform as different investigators reported contradictory findings when working with different viruses and cell types. It would not be obvious to one skilled in the art that a substance such as a sulphated polysaccharide that is an effective inhibitor of one virus would demonstrate similar efficacy against another virus.”
In the light of the above, the present invention now provides for a carrageenan- and/or fucoidan-based antiviral composition suitable in the prophylactic or therapeutic treatment of respiratory viral infections caused by members of the paramyxoviridae, orthomyxoviridae, adenoviridae and/or coronaviridae families. Contrary to the disclosure of Fujisawa H. et al. (1987, J. gen. Virol. 68, 425-423), who report that intranasal administration of carrageenan did not reduce the influenza A virus titer in mice but on the contrary even enhanced the animals' susceptibility to the virus depending on the amount of virus used for infection, it was now surprisingly found that carrageenan, in particular iota- and kappa-carrageenan, has indeed antiviral efficacy against various members of the orthomyxoviridae, paramyxoviridae, adenoviridae and coronaviridae.
Additionally, it was surprisingly found that fucoidan, particularly the high molecular weight fucoidan (HWMF) fraction, has antiviral efficacy against various members of the orthomyxoviridae and paramyxoviridae.
Accordingly, the present invention aims at providing an antiviral pharmaceutical composition suitable for the prevention or treatment of respiratory tract infections caused by a virus selected from the group consisting of orthomyxovirus, paramyxovirus, adenovirus and coronavirus, as well as for diseases or pathological conditions associated with such primary viral infections, such diseases or conditions comprising secondary viral or bacterial infections as well as bodily symptoms typically associated with any such primary or secondary infection including symptoms such as fever, pain, dizziness, shivering, sweating, and/or dehydration.